Special protein helps maintain an efficient brain

May 19, 2009 --
MADISON - The instruction manual for maintaining an efficient brain may
soon include a section on synaptotagmin-IV (Syt-IV), a protein known to
influence learning and memory, thanks to a study by University of
Wisconsin-Madison researchers.

The
study showed that Syt-IV keeps the strength of synapses - connections
between nerve cells where communication occurs - within a useful range
of neither too strong nor too weak.

Synapses' ability to adjust over time by becoming bigger and stronger
or smaller and weaker - their plasticity - is at the heart of
remembering, forgetting and learning. A delicate balance is required
for this optimal brain plasticity.

The study appears in Nature Neuroscience's advanced online publication on May 17.

The
findings may be useful in the future for treating neurodegenerative
disorders such as Alzheimer's disease and Parkinson's disease as well
as epileptic seizures. Early stages of these disorders may stem from
synaptic deficits.

"If a drug or genetic treatment could be
designed to control Syt-IV expression and modify its effect on other
key players involved in synaptic function, synapses might work better,"
says senior author Edwin R. Chapman, a Howard Hughes Medical Institute
professor at the UW-Madison School of Medicine and Public Health (SMPH).

Camin Dean, a postdoctoral fellow in Chapman's physiology department laboratory at the SMPH, did most of the work on the study.

The
scientists have been studying synaptotagmins for several years, making
great strides in understanding their role in releasing
neurotransmitters and neuropeptides at both the sending and receiving
sides of the synapse. The team is particularly interested in the way
neurotransmitter-filled sacs, or vesicles, work at the nerve terminals.

In
exploring Syt-IV, known for fluctuating up and down during the course
of a typical day, the researchers first studied it in a cell culture
and then in mice in which the protein had been knocked out. These
animals usually show learning deficits.

"We quickly found that
Syt-IV strongly affects multiple aspects of signal transmission, both
pre- and post-synaptically," says Chapman, adding that the protein was
not located where it was expected to be.

The researchers also
performed standard experiments on the mice to test a phenomenon called
long-term potentiation (LTP), the primary synapse-strengthening
mechanism that promotes learning and memory.

"When we stimulate
brain pathways heavily with this experiment, we see that synapses are
reinforced and produce bigger responses," says Chapman. "The synapses
remember the stimulation, they learn something from it and we can see
evidence of that."

Despite having learning disabilities, the Syt-IV-free mice produced improved LTP. In fact, it was too high.

"If
synapses are tweaked to the max, as they were in this case, they lose
plasticity and don't work well," says Chapman. "The overload also can
lead to seizures."

The researchers believe that Syt-IV serves as
a way to maintain synaptic homeostasis - or internal equilibrium - by
reigning in LTP to a normal level.

The protein does its work
indirectly by regulating brain-derived neurotrophic factor (BDNF), a
growth factor essential for long-term nerve cell well-being. In recent
years, BDNF also has been shown to affect synapses.

In the
experiments, Syt-IV pulled down elevated LTP by restricting the release
of BDNF on the receiving side of the synapse, gearing down synaptic
activity.

"Syt-IV dynamically regulates LTP as it goes up and
down, holding the activity in balance," he says. "For plasticity, you
need a good dynamic range of synaptic activity - from low to high."